Human papillomavirus (HPV) infections will continue to be ubiquitous and frequent in patient populations despite the recent development of protective virus-like particle (VLP) vaccines. Currently, the vaccine targets 4 of the 15+ HPV types that are associated with epithelial malignancies, and provides protection only to the vaccine-related types with minimal cross-protection to related types. HPV-associated malignancies include cancers of the cervix, anogenital mucosa, oral mucosa and skin, with cervical cancer predominating at 500,000 deaths per year world-wide. Post-infection therapeutic vaccines that activate T-cell-mediated immunity therefore will be a key adjunct method to control existing HPV-associated disease. However, critical questions regarding the mechanism of immunological clearance of HPV infections remain unanswered. For example, we do not yet know: (i) which viral antigens can induce the most effective immune-mediated clearance of HPV infections; (ii) which viral epitopes produce the most potent protective and therapeutic immunity to papillomavirus infections and associated cancer; (iii) what role CD8+ T-cells play in control and clearance of HPV infections, and (iv) why naturally developing CMI responses to persistent papillomavirus infections fail to clear these viral-associated tumors and cancers. The long range goal of our research program is directed at answering these questions. To better understand host immune responses to papillomaviruses (PVs), we need effective preclinical models of natural papillomavirus (PV) infection with subsequent progression to PV-associated malignancies. Unfortunately, no small inbred rodent animal model of PV infections exists for immunological and virological studies. In the absence of mouse and rat PV model systems, the most effective small laboratory animal model is the domestic rabbit which is susceptible to infection by the cutaneous-tropic cottontail rabbit PV (CRPV) and the mucosotropic rabbit oral PV (ROPV). We have recently developed a novel HLA-A2.1 transgenic rabbit model to assist our studies on key HPV and CRPV epitopes that trigger CD8 T-cell-mediated immunity. We will pursue 3 critical aims in this renewal application as follows: 1) Assess the role of therapeutic and protective CMI-induced immunity to papillomaviral tumor antigens in a rabbit papillomavirus tumor model. 2) Determine the role of HLA-A2.1 restricted papillomaviral antigen epitopes that trigger CD8 T-cell protective and therapeutic anti-tumor immunity, and 3) Determine the mechanism of immunological responses to viral tumor antigens that lead to therapeutic resolution and/or enhancement of papillomaviral tumors and cancers. Upon conclusion of these experiments, it is our expectation that the combination of work proposed in aims 1, 2 and 3 will translate directly into the design of improved therapeutic vaccines for HPV infections in patient populations.